Diabetes, which is comprised of various disorders of metabolism, mainly that of carbohydrate metabolism caused by relative or absolute lack of insulin activity, is roughly classified into two types. One is insulin-dependent diabetes mellitus (type I: IDDM), and the other is noninsulin-dependent diabetes mellitus (type II: NIDDM). The onset of insulin-dependent diabetes mellitus is brought by hyposecretion of insulin as a result of the progressive disruption of β cells in pancreatic islet caused by an auto-immune mechanism. On the other hand, the onset of noninsulin-dependent diabetes mellitus is triggered when insulin resistance caused by obesity is added to diatheses of inherited hyposecretion of insulin and insulin resistance in skeletal muscles. This noninsulin-dependent diabetes mellitus makes up 95% or more of whole diabetes.
So far, examples of diabetes where its cause is elucidated at a gene level include insulin abnormality, insulin receptor abnormality, glucokinase gene abnormality (MODY2) and diabetes caused by abnormality of mitochondrial DNA. In addition, locations of MODY1, MODY3, NIDDM1 and NIDDM2 genes on a chromosome have been mapped by linkage analysis. Meanwhile, a NOD (non-obese diabetic) mouse, diabetes-inducing transgenic mouse being introduced with diabetogenic gene wherein a human insulin gene promoter is fused with a thermal shock protein 70 gene attached to a lower part of the promoter (Japanese Laid-Open Patent Application No. 9-28384), a transgenic fish having a humanized insulin gene being modified to secrete human insulin (Published Japanese Translation of PCT International Publication No. 10-504725), and a transgenic animal model for type II diabetes mellitus (Published Japanese Translation of PCT International Publication No. 10-507084) have been proposed as model animals for diabetes.
On the other hand, it has been found that genome imprinting is a gene expression mode only observed in mammals as far as higher vetebrates are concerned, and plays a crucial role in ontogeny, growth, behavior and the like of mammals, and affects a certain kind of gene disease and oncogenesis in human being. This genome imprinting is known as a phenomenon where paternal and maternal genomes play functionally different roles in ontogeny (Cell 45, 127, 1986, Cell 37, 179, 1984, Nature 315, 496, 1985).
The above-mentioned genome imprinted gene has been found in 1991 at the first time (Cell 64, 849, 1991), revealing that there are gene populations that exhibit paternal and maternal expressions, and it has been already reported that more than 30 genes of this type are present in a human and a mouse. Further, understanding of the molecular mechanism of genome imprinting that affects ontogeny, growth and behavior of mammals makes it possible to elucidate direct or indirect causes of fetal death, neonatal death, overgrowth, growth retardation, behavioral disturbance [Nature 315, 496, 1985, Frontiers in Molecular Biology, p 118, (IRL Press, Oxford, 1997)] induced by overexpression or lack of expression of a specific imprinted gene (population) and some human hereditary diseases (Trends Genet 5, 331, 1989, Semin Cancer Biol 3, 151, 1992, Hum Mol Genet 4, 1757, 1995, Trends Genet 13, 436, 1997).
Conventionally known separating methods of such genome imprinted gene include a method utilizing sexual differences in metylation level in genomic DNA (RLGS; restriction landmark genomic scanning), and a method utilizing the difference in gene (cDNA) expression from male and female genomes (differential display method, allelic message display method, unichromosomal transfer method, and subtraction-hybridization method). The subtraction-hybridization method, which is developed by the inventors, is a separating method of Peg (a gene population expressed only from paternal genomes) and Meg (a gene population expressed only from maternal genomes) that utilizes the difference in gene expression between a parthenogenetic embryo having maternal genomes only or an androgenetic embryo having paternal genomes only and a normal fertilized embryo. By the subtraction-hybridization method, the inventors have separated a Meg 1 gene and determined the base sequence of this imprinted Meg 1 gene, and already elucidated that the gene is functionally identical to the known Grb10 gene (Oncogene 10, 1621-1630, 1995) (Proc. Natl. Acad. Sci. USA. 95, 1102-1107, 1998).
After insulin and insulin-like growth factor (IGF) bind to an insulin receptor and an IGF1 receptor respectively, tyrosin residues of these receptors are phosphorylated, and cell proliferation and carbohydrate metabolism are adjusted by transmitting this phosphorylation to downstream proteins (IRS-1 to IRS-4, etc). An object of the present invention is to provide a model mammal for diabetes onset being useful for the elucidation of an onset mechanism of diabetes caused by a blockage of signal transduction from insulin, and for the development of a remedy for said diabetes, and to provide a screening method of a remedy for said diabetes, and the like.